An amide compound, a preparation method and application thereof

Abstract

The application provides an amide compound and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The amide compound provided by the application is specifically an N-cinnamoyl-2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carboxamide compound. Different substituted indigo and carbamoyl hydrazine are subjected to oil bath reaction under the action of a catalyst to obtain a product 1; different substituted cinnamic acid, the product 1, sodium hydride and N,N'-carbonyldiimidazole are subjected to reaction in a solvent to obtain the N-cinnamoyl-2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carboxamide compound. The amide compound obtained by the method, and a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof have high efficiency and a broad-spectrum anti-inflammatory use.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to an amide compound, its preparation method, and its application. Background Technology

[0002] Acute lung injury (ALI) is a life-threatening lung disease characterized by increased lung epithelial permeability, alveolar damage, inflammatory cell infiltration, and pulmonary edema. ALI is caused by a variety of factors, including lipopolysaccharide, viruses, bacteria, and mycoplasma. The high mortality rate of ALI is due to multi-organ respiratory failure caused by local or systemic inflammatory responses and secondary bacterial infections resulting from weakened immune function. Current treatment options for severe pneumonia include antibiotics, glucocorticoids, and anti-inflammatory steroids. It has been reported that a higher proportion of pneumonia patients are receiving unnecessary antibiotic treatment, which may lead to higher antibiotic resistance. A complex network of inflammatory factors and chemokines plays a crucial role in mediating, amplifying, and prolonging acute lung injury. Therefore, inhibiting the release of inflammatory factors has become an important approach to treating acute lung injury. Dexamethasone is a glucocorticoid anti-inflammatory drug that inhibits a variety of inflammatory factors. However, steroids have serious side effects, and long-term use may lead to sequelae such as glaucoma, hypertension, increased risk of infection, and osteoporosis. Therefore, developing low-toxicity and highly effective nonsteroidal anti-inflammatory drugs is of great significance for the clinical treatment of ALI. Summary of the Invention

[0003] The purpose of this invention is to provide an amide compound, its preparation method, and its application, in order to solve the technical problem that the long-term use of existing steroid anti-inflammatory drugs leads to various sequelae and fails to meet the requirements of low toxicity and high-efficiency anti-inflammatory use.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides an N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound, the structural formula of which is as follows: Formula I:

[0006]

[0007] Wherein, R1 is hydrogen, halogen, alkoxy, or acetoxy; R2 is hydrogen, alkyl, or halogen.

[0008] Furthermore, the N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound is selected from one of the following structural formulas:

[0009] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0010] This invention provides a method for preparing N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds, comprising the following steps:

[0011] 1) Different substituted indigos were reacted with carbamoyl hydrazine in an oil bath under the action of a catalyst to obtain product 1;

[0012] 2) Different substituted cinnamic acids, product 1, sodium hydride and N,N'-carbonyldiimidazole were reacted in a solvent to obtain N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds;

[0013] The different substituted indigos have the following structure II, the different substituted cinnamic acid have the following structure III, and product 1 has the following structure IV:

[0014]

[0015] Formula II Formula III Formula IV

[0016] Where R1 is hydrogen, halogen, alkoxy, or acetoxy; and R2 is hydrogen, alkyl, or halogen.

[0017] Furthermore, the molar volume ratio of the different substituted indigo, carbamoyl hydrazine and the catalyst is 1.0 mmol: 1.0~1.4 mmol: 0.1~0.3 mL; the catalyst is glacial acetic acid.

[0018] Furthermore, the oil bath reaction temperature is 80~110℃, and the oil bath reaction time is 9~12h.

[0019] Furthermore, the oil bath reaction is carried out in a solvent comprising any one of anhydrous ethanol, methanol, and propylene glycol.

[0020] Furthermore, the molar ratio of the different substituted cinnamic acids, product 1, sodium hydride, and N,N'-carbonyldiimidazole is 1.0~1.3:0.8~1.1:1.3~1.8:1.0~1.3, and the molar volume ratio of the different substituted cinnamic acids and the solvent is 1.0~1.3 mmol:4~6 mL.

[0021] Furthermore, in step 2), the reaction temperature is 20~30℃, the reaction time is 3~5h, and the solvent is dichloromethane.

[0022] The present invention also provides the use of N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds and their pharmaceutically acceptable salts, hydrates, solvates and prodrugs in the preparation of pharmaceutical formulations for treating inflammation-related diseases caused by overexpression of inflammatory factors, wherein the inflammation-related disease caused by overexpression of inflammatory factors is acute lung injury.

[0023] Furthermore, the pharmaceutical preparation is an injection, tablet, capsule, aerosol, suppository, film, drop pill, ointment, controlled-release agent, sustained-release agent, or nano-preparation.

[0024] The beneficial effects of this invention are:

[0025] The compound of formula (I) obtained by this invention can treat acute lung injury caused by inflammation. Biological experiments have verified that the compound has anti-inflammatory activity, and in particular, it can be used in the preparation of pharmaceutical formulations for treating acute lung injury caused by excessive expression and release of IL-6 or TNF-α.

[0026] The synthesis method of the present invention is simple, the process is short, and the product yield is 30-60%. Attached Figure Description

[0027] Figure 1 A dose-response diagram showing the effect of the compound on inhibiting LPS-stimulated IL-6 release from J774A.1 cells;

[0028] Figure 2 A dose-response diagram showing the effect of the compound on inhibiting the release of TNF-α from LPS-stimulated J774A.1 cells;

[0029] Figures 3-8 This is a diagram illustrating the physiological changes in rats with acute lung injury caused by compound 6 in Example 6.

[0030] in, Figure 3 The expression level of IL-6 in bronchoalveolar lavage fluid, Figure 4 The expression level of IL-6 in serum, Figure 5 Serum TNF-α expression level, Figure 6 The total protein content in bronchoalveolar lavage fluid, Figure 7 The number of neutrophils in bronchoalveolar lavage fluid, Figure 8 The wet weight / dry weight ratio (W / D) is used.

[0031] Figure 9 This is a diagram showing the pathological changes in lung tissue during the relief of acute lung injury by compound 6 in Example 6. Detailed Implementation

[0032] This invention provides an N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound, the structural formula of which is as follows: Formula I:

[0033]

[0034] Wherein, R1 is hydrogen, halogen, alkoxy, or acetoxy; R2 is hydrogen, alkyl, or halogen.

[0035] In this invention, R1 is preferably F, Cl, or Br, more preferably Br; R2 is preferably C1~C2. 10 The alkyl, F, Cl or Br elements are preferred, and more preferably C3 to C8 alkyl or Br elements.

[0036] In this invention, the N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound is selected from one of the following structural formulas:

[0037] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Preferred , or Further preferred .

[0038] In this invention, the N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds are specifically the following compounds 1 to 40:

[0039]

[0040]

[0041] In this invention, the names corresponding to compounds 1 to 40 are as follows:

[0042] The chemical name of compound 1 is: N-cinnamyl-2-(Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0043] The chemical name of compound 2 is: N-(E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0044] The chemical name of compound 3 is: N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0045] The chemical name of compound 4 is: N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0046] The chemical name of compound 5 is: 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide;

[0047] The chemical name of compound 6 is: N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0048] The chemical name of compound 7 is: N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0049] The chemical name of compound 8 is: 2-methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0050] The chemical name of compound 9 is: 4-(((E)-3-oxo-3-(2-(((Z)-2-oxindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenyl acetate;

[0051] The chemical name of compound 10 is: 3-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenyl acetate;

[0052] The chemical name of compound 11 is: 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide;

[0053] The chemical name of compound 12 is: N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0054] The chemical name of compound 13 is: N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0055] The chemical name of compound 14 is: N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0056] The chemical name of compound 15 is: 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide;

[0057] The chemical name of compound 16 is: N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0058] The chemical name of compound 17 is: N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0059] The chemical name of compound 18 is: 2-methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0060] The chemical name of compound 19 is: 4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0061] The chemical name of compound 20 is: 3-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0062] The chemical name of compound 21 is: 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide;

[0063] The chemical name of compound 22 is: N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0064] The chemical name of compound 23 is: N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0065] The chemical name of compound 24 is: N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0066] The chemical name of compound 25 is: 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide;

[0067] The chemical name of compound 26 is: N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0068] The chemical name of compound 27 is: N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0069] The chemical name of compound 28 is: 2-methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0070] The chemical name of compound 29 is: 4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0071] The chemical name of compound 30 is: 3-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0072] The chemical name of compound 31 is: 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide;

[0073] The chemical name of compound 32 is: N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0074] The chemical name of compound 33 is: N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0075] The chemical name of compound 34 is: N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0076] The chemical name of compound 35 is: 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide;

[0077] The chemical name of compound 36 is: N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0078] The chemical name of compound 37 is: N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide;

[0079] The chemical name of compound 38 is: 2-methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0080] The chemical name of compound 39 is: 4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate;

[0081] The chemical name of compound 40 is 3-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate.

[0082] This invention provides a method for preparing N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds, comprising the following steps:

[0083] 1) Different substituted indigos were reacted with carbamoyl hydrazine in an oil bath under the action of a catalyst to obtain product 1;

[0084] 2) Different substituted cinnamic acids, product 1, sodium hydride and N,N'-carbonyldiimidazole were reacted in a solvent to obtain N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds;

[0085] The different substituted indigos have the following structure II, the different substituted cinnamic acid have the following structure III, and product 1 has the following structure IV:

[0086]

[0087] Formula II Formula III Formula IV

[0088] Where R1 is hydrogen, halogen, alkoxy, or acetoxy; and R2 is hydrogen, alkyl, or halogen.

[0089] In this invention, R1 is preferably F, Cl, or Br, more preferably Br; R2 is preferably C1~C2. 10 The alkyl, F, Cl or Br elements are preferred, and more preferably C3 to C8 alkyl or Br elements.

[0090] In this invention, the synthetic route for the compound of formula I is as follows:

[0091]

[0092] In this invention, the molar volume ratio of the different substituted indigo, carbamoyl hydrazine and catalyst is 1.0 mmol: 1.0~1.4 mmol: 0.1~0.3 mL, preferably 1.0 mmol: 1.1~1.3 mmol: 0.1~0.2 mL, and more preferably 1.0 mmol: 1.2 mmol: 0.2 mL.

[0093] In this invention, the catalyst is preferably glacial acetic acid.

[0094] In this invention, the temperature of the oil bath reaction is 80~110℃, preferably 85~105℃, and more preferably 90~100℃; the time of the oil bath reaction is 9~12h, preferably 10~11h, and more preferably 10h.

[0095] In this invention, the oil bath reaction is carried out in a solvent, which includes any one of anhydrous ethanol, methanol and propylene glycol, preferably anhydrous ethanol.

[0096] In this invention, the preparation method of the different substituted cinnamic acids is as follows: benzaldehyde with different substituents and malonic acid are reacted in an oil bath in a solvent, and the resulting product is precipitated after adjusting the pH value, filtered, and washed to obtain the different substituted cinnamic acids; the molar ratio of benzaldehyde with different substituents and malonic acid is 1.0:1.8~2.2, preferably 1.0:2.0.

[0097] In this invention, the molar volume ratio of the different substituted cinnamic acid and the solvent is 1.0~1.3mmol:4~6mL, preferably 1.1mmol:5mL.

[0098] In this invention, the temperature of the oil bath reaction is 90~110℃, preferably 100℃; the time of the oil bath reaction is 9~11h, preferably 10h; and the pH is adjusted to 2~3, preferably 2.

[0099] In this invention, the molar ratio of the different substituted cinnamic acid, product 1, sodium hydride, and N,N'-carbonyldiimidazole is 1.0~1.3:0.8~1.1:1.3~1.8:1.0~1.3, preferably 1.1~1.2:0.9~1.0:1.4~1.6:1.1~1.2, and more preferably 1.1:1.0:1.5:1.1.

[0100] In this invention, the molar volume ratio of the different substituted cinnamic acid and the solvent is 1.0~1.3mmol:4~6mL, preferably 1.1mmol:5mL.

[0101] In this invention, in step 2), the reaction temperature is 20~30℃, preferably 22~28℃, more preferably 25℃; the reaction time is 3~5h, preferably 4h; and the solvent is preferably dichloromethane.

[0102] The present invention also provides the use of N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds and their pharmaceutically acceptable salts, hydrates, solvates and prodrugs in the preparation of pharmaceutical formulations for treating inflammation-related diseases caused by overexpression of inflammatory factors, wherein the inflammation-related disease caused by overexpression of inflammatory factors is acute lung injury.

[0103] In this invention, the pharmaceutical preparation is an injection, tablet, capsule, aerosol, suppository, film, drop pill, ointment, controlled-release agent, sustained-release agent, or nano-preparation, preferably an injection, tablet, capsule, aerosol, suppository, film, drop pill, or ointment.

[0104] In this invention, the pharmaceutical formulation is a pharmaceutical composition containing N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds and their pharmaceutically acceptable salts, hydrates, solvates and prodrugs, wherein the carrier of the pharmaceutical composition comprises a binder, lubricant, disintegrant, solubilizer, diluent, stabilizer, suspending agent, colorant, flavoring agent, preservative, solvent and matrix.

[0105] In this invention, the pharmaceutical preparation can be administered orally or via parenteral route (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0106] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0107] The structural formulas of the compounds in Examples 1-40 of this invention are shown in Table 1 below:

[0108] Table 1 Structural formulas of Examples 1-40

[0109]

[0110]

[0111] Example 1

[0112] N-Cinnamyl-2-(Z)-2-oxoindole-3-yl)hydrazine-1-carboxamide

[0113] Step 1: Synthesis of Cinnamic Acid

[0114] 1.0 mmol of benzaldehyde with different substituents was dissolved in 2 mL of pyridine, and 2.0 mmol of malonic acid was added. The mixture was reacted in an oil bath at 100 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, ice water was added, and the pH was adjusted to 2 with hydrochloric acid. Solid precipitated upon standing. The mixture was then filtered under pressure, washed with ice-cold anhydrous ethanol and distilled water, and the filter cake was collected and dried to obtain pure cinnamic acid with different substituents.

[0115] Among them, benzaldehyde with different substituents R1 is H;

[0116] Among them, different substituted cinnamic acid R1 is H.

[0117] Step 2: (Z)-2-(2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0118] Dissolve 1.0 mmol of different substituted indigos in 4 mL of anhydrous ethanol, add 1.2 mmol of carbamoyl hydrazide or thiocarbamate, and use glacial acetic acid as a catalyst. React in an oil bath at 90 °C for about 10 h. After the reaction is complete, cool to room temperature, add ice water, and allow to stand to precipitate. Filter under pressure, wash with ice-cold anhydrous ethanol and distilled water, collect the filter cake, and dry to obtain the pure product.

[0119] Among them, different substitutions of indigo R2 is H.

[0120] Step 3: N-cinnamyl-2-(Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0121] In a 25 mL round-bottom flask, 1.1 mmol of substituted cinnamic acid, 1.0 mmol of ((Z)-2-(2-oxindol-3-ylidene)hydrazine-1-carboxamide, 1.5 mmol of sodium hydride, and 1.1 mmol of CDI (N,N′-carbonyldiimidazole) synthesized in steps one and two were added sequentially to 5 mL of dichloromethane. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the dichloromethane was evaporated to dryness, and the mixture was extracted with EA. The organic layer was washed three times with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the EA was evaporated to dryness under reduced pressure. Column chromatography analysis revealed that the product was N-cinnamyl-2-(Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide, with a yield of 60%.

[0122] 1 H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.18 (d, J= 7.9 Hz, 1H),7.93 – 7.72 (m, 5H), 7.50 (s, 4H), 7.34 (s, 1H). LC-MS m / z: 365.2 (M+CH3OH) - calcd for C 18 H 14 N4O3: 334.11.

[0123] The synthesis methods for Examples 2-40 are the same as those for Example 1.

[0124] Example 2

[0125] N-(E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide 1 HNMR (400 MHz, DMSO) δ 11.56 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.88 (d, J =15.7 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.71 (dd, J = 12.2, 6.3 Hz, 3H), 7.47(t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 3.83(s, 3H). LC-MS m / z: 365.2 (M+H) + calcd for C 19 H 16 N4O4: 364.12. Yield 55%.

[0126] Example 3

[0127] N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0128] 1 H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H),7.92 – 7.79 (m, 3H), 7.49 (t, J= 7.4 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.37– 7.33 (m, 2H), 7.29 (s, 1H), 7.08 (dd, J = 8.0, 2.1 Hz, 1H), 3.84 (s, 3H).LC-MS m / z: 395.2 (M+CH3OH) - calcd for C 19 H 16 N4O4: 364.12. Yield 58%.

[0129] Example 4

[0130] N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0131] 1 H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 28.0, 11.6 Hz, 2H), 7.69 (d, J = 15.6 Hz, 1H), 7.50 – 7.44 (m,1H), 7.36 – 7.28 (m, 3H), 7.08 (d, J = 8.5 Hz, 1H), 3.86 – 3.79 (m, 6H). LC-MS m / z: 425.20 (M+CH3OH) - calcd for C 20 H 18 N4O5: 394.13. Yield 36%.

[0132] Example 5

[0133] 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide

[0134] 1 H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.84 (dd, J= 28.0, 11.6 Hz, 2H), 7.69 (d, J = 15.6 Hz, 1H), 7.50 – 7.44 (m,1H), 7.36 – 7.28 (m, 3H), 7.08 (d, J = 8.5 Hz, 1H), 3.86 – 3.79 (m, 6H). LC-MS m / z: 455.1 (M+CH3OH) - calcd for C 21 H 20 N4O6: 424.14. Yield 58%.

[0135] Example 6

[0136] N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0137] 1 H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H),8.02 (s, 1H), 7.85 (s, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.76 (s, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H). LC-MS m / z: 433.1 (M+CH3OH) - , calcdfor C 18 H 12 Cl2N4O3: 402.03. Yield 60%.

[0138] Example 7

[0139] N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0140] 1 H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H),7.92 – 7.76 (m, 5H), 7.57 (d, J= 8.4 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.34(t, J = 7.5 Hz, 1H). LC-MS m / z: 399.1 (M+CH3OH) - calcd for C 18 H 13 ClN4O3: 368.07. Yield 55%.

[0141] Example 8

[0142] 2-Methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0143] 1 H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H),7.88 (s, 1H), 7.79 (d, J = 12.2 Hz, 2H), 7.49 (s, 2H), 7.36 (d, J = 14.1 Hz, 2H), 7.22 (d, J = 4.5 Hz, 1H), 3.85 (s, 3H), 2.28 (s, 3H). LC-MS m / z: 453.2(M+CH3OH) - calcd for C 21 H 18 N4O6: 422.12. Yield 56%.

[0144] Example 9

[0145] 4-(((E)-3-oxo-3-(2-(((Z)-2-oxindol-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenyl acetate

[0146] 1 H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 15.8 Hz, 1H), 7.83 – 7.78 (m, 3H), 7.49 (t, J= 7.8 Hz, 1H),7.38 – 7.32 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 2.31 (s, 3H). LC-MS m / z: 395.2(M+H) + calcd for C 20 H 16 N4O5: 393.11. Yield 30%.

[0147] Example 10

[0148] 3-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenyl acetate

[0149] 1 H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.83 (dd, J = 16.8, 10.9 Hz, 3H), 7.64 (d, J = 7.7 Hz, 1H), 7.55 – 7.44 (m,3H), 7.34 (t, J = 7.5 Hz, 1H), 7.25 (s, 1H), 2.31 (s, 3H). LC-MS m / z: 423.2(M+CH3OH) - calcd for C 20 H 16 N4O5: 393.11. Yield: 48%.

[0150] Example 11

[0151] 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide

[0152] 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H),7.95 – 7.88 (m, 2H), 7.82 (d, J = 15.8 Hz, 1H), 7.75 (dd, J = 6.3, 2.8 Hz, 2H), 7.51 (dd,J = 8.2, 5.8 Hz, 4H). LC-MS m / z: 399.1 (M+CH3OH) - , calcd forC 18 H 13 ClN4O3: 368.07. Yield 49%.

[0153] Example 12

[0154] N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0155] 1 H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.90 (dd, J = 10.8, 9.1 Hz, 2H), 7.70 (dd, J = 12.1, 10.4 Hz, 3H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H). LC-MS m / s:429.1(M+CH3OH) - calcd for C 19 H 15 ClN4O4: 398.08. Yield: 40%.

[0156] Example 13

[0157] N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0158] 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H),7.93 – 7.76 (m, 3H), 7.51 (dd, J = 8.7, 1.9 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.82(s, 3H). LC-MS m / z: 397.0, 429.1 (M+H) - (M+CH3OH) - calcd for C 19 H 15 ClN4O4: 398.08. Yield 41%.

[0159] Example 14

[0160] N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0161] 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.15 (d, J = 8.6 Hz, 1H),7.98 – 7.83 (m, 2H), 7.68 (d, J = 15.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H),7.37 – 7.27 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 3.83 (s, 6H). LC-MS m / z: 459.0(M+CH3OH) - calcd for C 20 H 17 ClN4O5: 428.09. Yield 36%.

[0162] Example 15

[0163] 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide

[0164] 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),7.96 – 7.83 (m, 2H), 7.72 (d, J = 15.5 Hz, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.08 (s, 2H), 3.86 (s, 7H), 3.74 (s, 3H). LC-MS m / z: 489.1 (M+CH3OH) - , calcdfor C 21 H 19 ClN4O6: 458.10. Yield 35%.

[0165] Example 16

[0166] N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0167] 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.15 (d, J = 8.6 Hz, 1H),7.98 – 7.83 (m, 2H), 7.68 (d, J = 15.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H),7.37 – 7.27 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 3.83 (s, 6H). LC-MS m / z: 467.0(M+CH3OH) - calcd for C 18 H 11 Cl3N4O3: 435.99. Yield 35%.

[0168] Example 17

[0169] N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0170] 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 20.7 Hz, 1H), 7.77 (d, J= 8.4 Hz,2H), 7.59 – 7.46 (m, 4H). LC-MS m / z: 433.1 (M+CH3OH) - calcd for C 18 H 12 Cl2N4O3: 402.03. Yield 52%.

[0171] Example 18

[0172] 2-Methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0173] 1 H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 16.7 Hz, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.55 – 7.48 (m, 2H), 7.39 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 2.30 (s, 3H). LC-MS m / z: 487.1 (M+CH3OH) - calcd for C 21 H 17 ClN4O6: 456.08. Yield 39%.

[0174] Example 19

[0175] 4-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0176] 1 H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.20 – 8.15 (m, 1H), 7.92 (d, J = 13.0 Hz, 2H), 7.86 – 7.75 (m, 3H), 7.53 (d, J = 8.4 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 2.31 (s, 3H). LC-MS m / z: 425.1 (M+H) - calcd for C 20 H 15 ClN4O5: 426.07. Yield 53%.

[0177] Example 20

[0178] 3-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate

[0179] 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 11.9, 9.0 Hz, 2H), 7.80 (d, J = 15.8 Hz, 1H), 7.64 (d, J = 7.7Hz, 1H), 7.53 (d, J = 8.1 Hz, 3H), 7.27 (d, J = 7.9 Hz, 1H), 2.31 (s, 3H).LC-MS m / z: 457.1 (M+CH3OH) - calcd for C 20 H 15 ClN4O5: 426.07. Yield 56%.

[0180] Example 21

[0181] 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide

[0182] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 37.8, 15.8 Hz, 2H), 7.75 (dd, J =6.4, 2.9 Hz, 2H), 7.65 (dd,J = 8.7, 2.2 Hz, 1H), 7.52 – 7.48 (m, 3H). Yield 52%.

[0183] Example 22

[0184] N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0185] 1 H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.15 – 8.01 (m, 2H), 7.89 (d, J = 15.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68 – 7.58 (m, 2H), 7.06 (d, J =8.6 Hz, 2H), 3.83 (s, 3H). LC-MS m / z: 473.1 (M+CH3OH) - calcd for C 19 H 15 BrN4O4: 442.03. Yield 45%.

[0186] Example 23

[0187] N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxyl

[0188] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 16.8 Hz, 2H), 7.64 (dd, J = 8.7, 2.1Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.07 (dd, J= 8.1, 2.0 Hz, 1H), 3.82 (s, 3H). LC-MS m / z: 473.1 (M+CH3OH) - calcd for C 19 H 15 BrN4O4: 442.03. Yield 48%.

[0189] Example 24

[0190] N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0191] 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.16 – 7.98 (m, 2H), 7.87 (d, J = 15.6 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.36 – 7.28 (m, 2H), 7.06 (d, J = 8.3Hz, 1H), 3.83 (s, 6H). LC-MS m / z: 503.1 (M+CH3OH) - calcd for C 20 H 17 BrN4O5: 472.04. Yield 47%.

[0192] Example 25

[0193] 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide

[0194] 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 8.15 – 8.00 (m, 2H), 7.86 (d, J = 15.7 Hz, 1H), 7.67 (dd, J = 25.3, 12.1 Hz, 2H), 7.07 (s, 2H), 3.85 (s,6H), 3.73 (s, 3H). LC-MS m / z: 533.1 (M+CH3OH) - calcd for C 21 H 19BrN4O6: 502.05. Yield 41%.

[0195] Example 26

[0196] N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0197] 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 8.03 (d, J = 14.9 Hz, 2H),7.83 (s, 2H), 7.75 (s, 2H), 7.64 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 2.37 (s,3H). LC-MS m / z: 513.0 (M+CH3OH) + calcd for C 18 H 11 BrCl2N4O3: 479.94. Yield 47%.

[0198] Example 27

[0199] N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0200] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.08 (dd, J = 17.2, 5.3 Hz,2H), 7.92 – 7.75 (m, 4H), 7.65 (dd, J = 8.7, 2.1 Hz, 1H), 7.56 (d, J = 8.4Hz, 2H). LC-MS m / z: 477.1 (M+CH3OH) - , 479.0 (M+CH3OH) + calcd for C 18 H 12 BrClN4O3: 445.95. Yield 57%.

[0201] Example 28

[0202] 2-Methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0203] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.09 (dd, J = 15.1, 5.4 Hz, 2H), 7.91 (d, J = 15.7 Hz, 1H), 7.78 (d, J = 15.7 Hz, 1H), 7.67 – 7.63 (m,1H), 7.49 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 8.3, 1.7 Hz, 1H), 7.22 (d, J =8.2 Hz, 1H), 3.85 (s, 3H), 2.29 (s, 3H). LC-MS m / z: 533.1 (M+CH3OH) + , calcdfor C 21 H 17 BrN4O6: 500.03. Yield 51%.

[0204] Example 29

[0205] 4-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0206] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.08 (dd, J = 19.4, 5.2 Hz, 2H), 7.91 (d, J = 15.8 Hz, 1H), 7.79 (dd, J = 12.1, 7.4 Hz, 3H), 7.64 (dd, J = 8.7, 1.9 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 2.30 (s, 3H). LC-MS m / z: 501.0(M+CH3OH) - calcd for C 20 H15 BrN4O5: 470.02. Yield 52%.

[0207] Example 30

[0208] 3-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate

[0209] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.09 (dd, J = 17.4, 5.4 Hz, 2H), 7.85 (dd, J = 38.6, 15.8 Hz, 2H), 7.67 – 7.62 (m, 2H), 7.53 (d, J = 7.8Hz, 2H), 7.26 (dd, J = 8.0, 1.4 Hz, 1H), 2.31 (s, 3H). LC-MS m / z: 503.1 (M+CH3OH) + calcd for C 20 H 15 BrN4O5: 470.02. Yield 41%.

[0210] Example 31

[0211] 2-((Z)-5-chloro-2-oxoindole-3-ylidene)-N-cinnamylhydrazine-1-carboxamide

[0212] 1 H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.08 (d, J = 6.7 Hz, 1H),7.87 (s, 2H), 7.74 (s, 2H), 7.65 (s, 1H), 7.49 (s, 3H), 7.27 (d, J = 7.4 Hz,1H), 2.38 (s, 4H). LC-MS m / z: 379.1 (M+CH3OH) - calcd for C 19 H 16 N4O3: 348.12. Yield 53%.

[0213] Example 32

[0214] N-((E)-3-(4-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0215] 1 H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.86 (d, J = 16.0 Hz, 1H), 7.73 – 7.60 (m, 4H), 7.27 (d, J = 7.4 Hz, 1H), 7.05 (d, J = 7.0 Hz, 2H), 3.83 (s, 4H), 2.36 (s, 3H). LC-MS m / z: 409.2 (M+CH3OH) - calcd for C 20 H 18 N4O4: 378.13. Yield 56%.

[0216] Example 33

[0217] N-((E)-3-(3-methoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0218] 1 H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 4.3 Hz, 2H), 7.63 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.27 (s, 2H), 7.09 – 7.03 (m, 1H), 3.82 (s, 3H), 2.37 (s, 3H). LC-MS m / z: 409.2 (M+CH3OH) - calcd for C 20 H 18 N4O4: 378.13. Yield 60%.

[0219] Example 34

[0220] N-((E)-3-(3,4-dimethoxyphenyl)acryloyl)-2-((Z)-2-oxindol-3-ylidene)hydrazine-1-carboxamide

[0221] 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 15.6 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.29 (dd, J = 17.2, 8.9 Hz, 4H), 7.06 (d, J = 8.4 Hz, 1H), 3.83 (s, 7H), 2.36 (s, 3H). LC-MS m / z: 439.2(M+CH3OH) - calcd for C 21 H 20 N4O5: 408.14. Yield 47%.

[0222] Example 35

[0223] 2-((Z)-2-oxoindole-3-ylidene)-N-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)hydrazine-1-carboxamide

[0224] 1 H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 15.6 Hz, 1H), 7.72 (d, J = 15.7 Hz, 1H), 7.64 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.07 (s, 2H), 3.85 (s, 6H), 3.73 (s, 3H), 2.37 (s, 3H). LC-MS m / z: 469.2 (M+CH3OH) - calcd for C 22 H 22 N4O6: 438.15. Yield 49%.

[0225] Example 36

[0226] N-((E)-3-(3,4-dichlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0227] 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 8.03 (d, J = 14.9 Hz, 2H),7.83 (s, 2H), 7.75 (s, 2H), 7.64 (s, 1H), 7.28 (d, J = 7.0 Hz, 1H), 2.37 (s,3H). LC-MS m / z: 447.1 (M+CH3OH) - calcd for C 19 H 14 Cl2N4O3: 416.04. Yield 45%.

[0228] Example 37

[0229] N-((E)-3-(4-chlorophenyl)acryloyl)-2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carboxamide

[0230] 1 H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 6.2 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.64 (s, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 2.37 (s, 3H). LC-MS m / z: 413.1 (M+CH3OH) - calcd for C 19 H 15 ClN4O3: 382.08. Yield 41%.

[0231] Example 38

[0232] 2-Methoxy-4-((E)-3-oxo-3-(2-((Z)-2-oxoindol-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0233] 1 H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 16.7 Hz, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.55 – 7.48 (m, 2H), 7.39 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 2.30 (s, 3H). LC-MS m / z: 467.1 (M+CH3OH) - calcd for C 22 H 20 N4O6: 436.14. Yield 43%.

[0234] Example 39

[0235] 4-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamate)prop-1-en-1-yl)phenylacetate

[0236] 1 H NMR (400 MHz, DMSO) δ 11.48 (d, J = 14.8 Hz, 1H), 8.03 (dd, J =16.1, 8.3 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.79 (dd, J = 12.1, 3.5 Hz, 2H), 7.62(d, J = 8.6 Hz, 1H), 7.25 (t, J = 8.9 Hz, 4H), 2.41 – 2.26 (m, 6H). LC-MS m / z: 405.1 (M+H) - calcd for C 21 H 18 N4O5: 406.13. Yield 55%.

[0237] Example 40

[0238] 3-((E)-3-oxo-3-(2-((Z)-2-oxoindole-3-ylidene)hydrazine-1-carbamoyl)prop-1-en-1-yl)phenylacetate

[0239] 1 H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 11.1 Hz, 2H), 7.63 (s, 2H), 7.55 – 7.48 (m, 2H), 7.27 (s, 2H), 2.34 (d, J = 19.6 Hz, 6H). LC-MS m / z: 406.0 (M+H) - calcd for C 21 H 18 N4O5: 406.13. Yield 59%.

[0240] Experimental Example 1

[0241] The dose-response relationship of the compound in Example 6 inhibiting the release of inflammatory factors from LPS-stimulated macrophages.

[0242] To test the dose-response relationship of the active compound inhibiting the release of IL-6 and TNF-α from LPS-stimulated J774A.1 cells, the specific method is as follows: 1.2 × 10 6 J774A.1 cells were cultured in DMEM medium at 37°C. After 24 hours, the culture medium was replaced, and the test compound was added for pretreatment. After half an hour, the cells were treated with 0.5 μg / mL LPS for another 24 hours. The culture medium was collected, and the levels of IL-6 and TNF-α were detected by ELISA. Cells were also collected to detect the total protein concentration. The ELISA results were compared by dividing the corresponding total protein concentration. The IL-6 content of the LPS control group was used as a calibration value of 100, and the average value and error value were calculated. Experimental results are shown below. Figure 1 and Figure 2 .

[0243] Experimental Example 2

[0244] The compound in Example 6 alleviated physiological changes in rats with acute lung injury.

[0245] A suspension of 0.5% sodium carboxymethyl cellulose and compound 6 was prepared for intraperitoneal administration. After anesthesia with ether, the trachea of ​​rats in each group was exposed. Except for the control group, 50 μL of 5 mg / kg LPS was slowly instilled into the trachea of ​​the other groups to induce acute lung injury. The control group received an equal volume of physiological saline in the same manner. The wound was sutured to establish an acute lung injury model. Twenty-four hours after model establishment, rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 5 mL / kg. The left lung was ligated after thoracotomy, and the right lung was lavaged with 1 mL of physiological saline. The lavage fluid was collected, and the same procedure was repeated three times.

[0246] After collection, bronchoalveolar lavage fluid (BALAF) was centrifuged at 1000 rpm for 5 minutes at 4°C. The supernatant was collected, and the protein concentration of the BALAF was measured. After centrifugation, the precipitate was resuspended in 50 μL of physiological saline, mixed thoroughly, and 20 μL was collected for counting the total number of cells in the BALAF using a Standard cell counter. Additionally, the upper lobe of the right lung was harvested, and after blotting off excess water with filter paper, the wet weight was measured. The tissue was then baked at 60°C for at least 48 hours until its weight no longer changed. The dry weight was then measured, and the wet / dry weight ratio (W / D) of the lung tissue was calculated to assess the degree of pulmonary edema. Experimental data are shown below. Figures 3-8 Both experimental results indicate that the compound can effectively alleviate acute lung injury in rats physiologically.

[0247] Figure 3 The expression level of IL-6 in bronchoalveolar lavage fluid, Figure 4 The expression level of IL-6 in serum, Figure 5 Serum TNF-α expression level, Figure 6 The total protein content in bronchoalveolar lavage fluid, Figure 7 The number of neutrophils in bronchoalveolar lavage fluid, Figure 8 It is the wet weight / dry weight ratio (W / D).

[0248] Experimental Example 3

[0249] Example 6: Pathological changes in lung tissue during compound treatment for acute lung injury.

[0250] Experimental data can be found Figure 9 In the normal control group, the alveolar cavities of rats were clear, structurally intact, and had smooth walls. After tracheal instillation of LPS to induce an acute lung injury model, the alveolar walls showed significant edema and thickening, with increased inflammatory cell infiltration. Treatment with the compound from Example 6 significantly reduced cell edema and thickening, and markedly decreased inflammatory cell infiltration, showing little difference from the normal group. This indicates that the compound can effectively alleviate lung tissue damage in acute lung injury.

[0251] As can be seen from the above embodiments, the present invention provides an amide compound, its preparation method, and its applications. The amide compounds obtained by the method of the present invention, as well as their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, have highly effective and broad-spectrum anti-inflammatory uses.

[0252] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound, characterized in that, The N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds are selected from one of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The method for preparing the N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound according to claim 1, characterized in that, Includes the following steps: 1) Different substituted indigos were reacted with carbamoyl hydrazine in an oil bath under the action of a catalyst to obtain product 1; 2) Different substituted cinnamic acids, product 1, sodium hydride and N,N'-carbonyldiimidazole were reacted in a solvent to obtain N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compounds; The different substituted indigos have the following structure II, the different substituted cinnamic acid have the following structure III, and product 1 has the following structure IV: Formula II, Formula III, Formula IV.

3. The preparation method according to claim 2, characterized in that, The molar volume ratio of the different substituted indigo, carbamoyl hydrazine and the catalyst is 1.0 mmol: 1.0~1.4 mmol: 0.1~0.3 mL; the catalyst is glacial acetic acid.

4. The preparation method according to claim 3, characterized in that, The oil bath reaction temperature is 80~110℃, and the oil bath reaction time is 9~12h.

5. The preparation method according to any one of claims 2 to 4, characterized in that, The oil bath reaction is carried out in a solvent, which includes any one of anhydrous ethanol, methanol, and propylene glycol.

6. The preparation method according to claim 5, characterized in that, The molar ratio of the different substituted cinnamic acids, product 1, sodium hydride, and N,N'-carbonyldiimidazole is 1.0~1.3:0.8~1.1:1.3~1.8:1.0~1.3, and the molar volume ratio of the different substituted cinnamic acids and the solvent is 1.0~1.3 mmol:4~6 mL.

7. The preparation method according to claim 2, 3, or 6, characterized in that, In step 2), the reaction temperature is 20~30℃ and the reaction time is 3~5h; the solvent is dichloromethane.

8. The use of the N-cinnamyl-2-((Z)-2-oxoindole-3-ethylene)hydrazine-1-carboxamide compound of claim 1 and its pharmaceutically acceptable salt in the preparation of a pharmaceutical formulation for treating inflammation-related diseases caused by overexpression of inflammatory factors, characterized in that, The inflammation-related disease caused by the overexpression of the inflammatory factors is acute lung injury.

9. The application according to claim 8, characterized in that, The pharmaceutical preparations are injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-preparations.

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